CARLSBAD, Calif., Sept. 21, 2013 /PRNewswire/ -- Isis Pharmaceuticals, Inc. (NASDAQ: ISIS) announced data from a Phase 2 study of ISIS-APOCIIIRx as a monotherapy in patients with familial chylomicronemia syndrome, or FCS. FCS is a rare orphan disease characterized by severely high triglyceride levels that affects an estimated 3,000 to 5,000 patients worldwide. These data were presented today by Dr. Daniel Gaudet at the National Lipid Association clinical lipid update meeting in Baltimore, MD. In this study, three patients with FCS treated with ISIS-APOCIIIRx achieved substantial reductions in triglycerides with all three patients achieving a triglyceride level below 500 mg/dL, which substantially reduces the risk of an acute pancreatic event. Patients also achieved substantial reductions in apoC-III and apoCIII-associated very low-density lipoprotein-cholesterol (VLDL-C) particles.

"Familial chylomicronemia is a rare and very serious genetic disorder that is often associated with triglyceride levels higher than 2,000 mg/dL. FCS patients with triglyceride levels this high often experience a significant number of health problems such as abdominal pain, eruptive fatty skin lesions, enlargement of the liver and spleen, and recurrent acute pancreatitis that often requires hospitalization. Current treatment approaches are usually ineffective in FCS patients and, as a result, FCS patients are required to severely limit their dietary fat intake. Despite these very restrictive measures, many FCS patients are still unable to lower their triglycerides enough to eliminate the risk of health problems. More effective triglyceride-lowering approaches are needed to treat FCS patients," said Daniel Gaudet, M.D., Ph.D., from the department of medicine, University of Montreal and scientific director, Genome Quebec Biobank Technology Center. "ISIS-APOCIIIRx has been shown to be a robust triglyceride-lowering agent in patients with moderately high to severely high triglycerides in multiple Phase 2 settings. These data presented today, although collected in a small number of patients, are also compelling and demonstrate the potential of ISIS-APOCIIIRx to produce dramatic triglyceride lowering in patients with FCS. Based on the comprehensive Phase 2 data for ISIS-APOCIIIRx, I am extremely encouraged about the therapeutic potential for ISIS-APOCIIIRx in patients with severely high triglycerides, especially for use in FCS patients who have very limited therapeutic options."

The Phase 2 open-label cohort was designed to assess the safety and activity of ISIS-APOCIIIRx in patients with severely high triglyceride levels (greater than 440 mg/dL) and a genetic confirmation of FCS. The data reported today is an analysis of the three FCS patients in the study all of whom had baseline triglyceride levels greater than 1,400 mg/dL and had completed 13 weeks of treatment with 300 mg of ISIS-APOCIIIRx. In this study, all three patients treated with ISIS-APOCIIIRx achieved substantial reductions in triglyceride levels with an average reduction of 69 percent. In addition, these patients experienced positive effects on other lipid parameters, including HDL-C, apoC-III and apoC-III-associated VLDL-C. Because FCS is an extremely rare genetic disorder affecting one to two people per million, clinical trials in this disease are generally quite small.

Table 1: ISIS-APOCIIIRx Produced Substantial Reductions of Triglycerides and ApoC-III as a Single Agent in a Phase 2 Study in Patients with FCS and Severely High Triglyceride Levels.

Patient 1

(485 mg/dL lowest TG)**

Patient 2

(251 mg/dL lowest TG)**

Patient 3

(234 mg/dL lowest TG)**

Mean %

Change

Baseline

(mg/dL)

Primary Endpoint (mg/dL)

* % Change

Baseline

(mg/dL)

Primary Endpoint (mg/dL)

*% Change

Baseline

(mg/dL)

Primary Endpoint (mg/dL)

*% Change

Triglycerides

1406

617

-56.2

2083

288

-86.2

2043

735

-64.0

-69

ApoC-III

18.9

5.5

-70.9

35.1

3.4

-90.4

19.8

3.5

-82.5

-81

VLDL-ApoC-III

12.2

4.5

-63.5

32.6

2.5

-92.2

16.8

2.3

-86.3

-81

HDL-C

16

24

+50

8

21

+162.5

14

17

+21.4

+78

Non-HDL-C

214

115

-46.5

327

84

-74.3

244

111

-54.5

-58

*Percent changes from baseline at primary endpoint (an average measurement of day 85 and 92)

** Lowest triglyceride level achieved during study

Consistent with the previously reported studies, ISIS-APOCIIIRx demonstrated a good safety profile and was well tolerated. The most common adverse event was injection site reactions, which were predominantly mild and typically resolved rapidly. There were no flu-like symptoms, no treatment-related elevations of liver enzymes greater than three times upper limit of normal, no abnormalities in renal function, no clinically meaningful changes in other laboratory values and no treatment related serious adverse events.

"Our focus is to bring ISIS-APOCIIIRx to the market for patients with severely elevated triglycerides. These patients cannot reduce their triglycerides to safe levels with currently available medicines. We are extremely pleased with the performance of ISIS-APOCIIIRx to date. These data presented today are particularly encouraging as we plan to pursue FCS as the initial indication for ISIS-APOCIIIRx in advance of our next indication in patients with severely elevated triglycerides. We believe that the significant unmet medical need for an effective triglyceride-lowering drug for patients with FCS and the robust, consistent effects we observe with ISIS-APOCIIIRx should enable us to rapidly move forward," said Richard Geary, Ph.D., senior vice president of development at Isis. "We look forward to discussing our Phase 3 plans with regulators and moving into a Phase 3 program next year in both patients with FCS and patients with severely high triglycerides."

FCS is a rare genetic disorder that affects approximately one to two out of a million people. The most common genetic cause of FCS is a defect in the lipoprotein lipase (LPL) gene, which results in extremely low levels of LPL activity and a significant reduction in the breakdown of triglycerides from the blood. In the study reported today, all three patients had the same genetic defect (P207L mutation) resulting in undetectable LPL activity.

ISIS-APOCIIIRx is an antisense drug being developed for the treatment of treat patients with severely high triglycerides either as a single agent or in combination with other triglyceride-lowering agents. ISIS-APOCIIIRx targets apoC-III, a protein produced by the liver that plays a central role in the regulation of serum triglycerides. This approach is validated by the fact that humans who produce low levels of apoC-III have lower levels of triglycerides and lower instances of cardiovascular disease. Humans with elevated levels of apoC-III have increased dyslipidemia associated with multiple metabolic abnormalities, such as insulin resistance and/or metabolic syndrome. In addition, the prevalence of type 2 diabetes is increased in patients with elevated triglycerides.

Conference Call

At 08:30 a.m. Eastern Time Monday, Sept. 23, 2013, Isis will conduct a live webcast and slide presentation conference call to discuss the positive Phase 2 data presented today. Interested parties may listen to the call by dialing 866-652-5200, or access the webcast with or without audio at www.isispharm.com. A webcast replay will be available for a limited time at the same address.

ABOUT ISIS PHARMACEUTICALS, INC.

Isis is exploiting its leadership position in antisense technology to discover and develop novel drugs for its product pipeline and for its partners. Isis' broad pipeline consists of 30 drugs to treat a wide variety of diseases with an emphasis on cardiovascular, metabolic, severe and rare diseases, including neurological disorders, and cancer. Isis' partner, Genzyme, is commercializing Isis' lead product, KYNAMRO™, in the United States for the treatment of patients with HoFH. Isis' patents provide strong and extensive protection for its drugs and technology. Additional information about Isis is available at www.isispharm.com.

ISIS PHARMACEUTICALS' FORWARD-LOOKING STATEMENT

This press release includes forward-looking statements regarding the discovery, development, and potential of drugs for cardiovascular diseases, and the development, activity, therapeutic potential and safety of ISIS-APOCIIIRx. Any statement describing Isis' goals, expectations, financial or other projections, intentions or beliefs, is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to certain risks and uncertainties, particularly those inherent in the process of discovering, developing and commercializing drugs that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such drugs. Isis' forward-looking statements also involve assumptions that, if they never materialize or prove correct, could cause its results to differ materially from those expressed or implied by such forward-looking statements. Although Isis' forward-looking statements reflect the good faith judgment of its management, these statements are based only on facts and factors currently known by Isis. As a result, you are cautioned not to rely on these forward-looking statements. These and other risks concerning Isis' programs are described in additional detail in Isis' annual report on Form 10-K for the year ended December 31, 2012 and its most recent quarterly report on Form 10-Q, which are on file with the SEC. Copies of these and other documents are available from the Company.

Isis Pharmaceuticals® is a registered trademark of Isis Pharmaceuticals, Inc. KYNAMRO™ is a trademark of Genzyme Corporation.